Bricanyl

Evidence From a Population Survey

Objectives: Increased bronchial responsiveness is a feature of symptomatic asthma, and it predicts the onset of wheezing. We have investigated the relationship between bronchial responsiveness and age in a population sample with an age range of 45 to 86 years.

Design: Cross-sectional population survey.

Setting: Population of Central Manchester, UK.

Participants: An age-stratified random sample of white adults aged [is greater than or equal to] 45 years old and living in Central Manchester. They were recruited from their primary care physician (general practitioner) lists. Patients with confusion and patients who were housebound were excluded.

Measurements: Respondents to a mail questionnaire were invited to attend a methacholine bronchial challenge performed using the Newcastle dosimeter method. Respondents with ischemic heart disease or respondents taking oral steroids, [Beta]-blockers, or anticholinergic medication were excluded.

Results: Of the 783 subjects contacted, 92.3% of the subjects responded, and 508 subjects returned enough information for us to deduce their suitability for the bronchial challenge. Of the 395 suitable subjects, 247 subjects participated (62.5% of those invited; 31.5% of the study population), and 208 participants completed the bronchial challenge. Participants were slightly younger than nonparticipants, but they were otherwise representative of the population. Increased bronchial responsiveness (provocative dose of methacholine causing a 20% fall in [FEV.sub.1] [is less than or equal to] 200 [micro]g) was present in 71 (34.1%) participants. Stepwise multiple regression analysis showed weak, independent, positive associations between bronchial responsiveness and age, and between bronchial responsiveness and the total immunoglobulin E level. There was an independent negative relationship between bronchial responsiveness and the airways caliber (expressed as standardized residuals; [R.sup.2] = 0.29).

Conclusions: We have found a high prevalence of increased bronchial responsiveness in this inner-city population of older adults. Bronchial responsiveness showed a weak independent positive association with age. (CHEST 1999; 115:660- 665)

Key words: aged; bronchial responsiveness; epidemiology

Abbreviations: DRS = dose-response slope; [PD.sub.20] = provocative dose of a substance causing a 20% fall in [FEV.sub.1]; SR = standardized residuals

Bronchial hyper-responsiveness is associated with respiratory symptoms and diagnosed asthma.[1] Although it is biologically plausible that a person's bronchial responsiveness can increase as the person ages, published population studies fail to agree whether such a relationsship exists.[2-8] We have measured bronchial responsiveness in an age-stratified random population sample of white adults aged 45 to 86 years old in order to further investigate the relationship between age and bronchial responsiveness.

MATERIALS AND METHODS

The study was approved by the Central Manchester Health Authority Ethical Committee. A random sample of adults aged [is greater than or equal to] 45 years old was selected from the practice lists of local primary care physicians (general practitioners) using random number tables. General practitioners identified those to be excluded from the study, which included patients who were non-Caucasian or housebound and patients with confusion or other major illnesses preventing participation, eg, a psychiatric disorder or a malignant disease. Non-Caucasians were excluded because of interracial differences in bronchial responsiveness.[9] During the last 12 months of recruitment, an increase in the number of older adults included in the study was achieved by discarding alternate selected people aged [is less than] 70 years old.

Eligible subjects were sent a short explanatory letter and a questionnaire concerning diagnosed asthma or chronic bronchitis, respiratory symptoms, smoking habits, ischemic heart disease, and current medications. Questions regarding respiratory symptoms were based on the Medical Research Council questionnaire.[10] Returned questionnaires were screened to identify those suitable for the methacholine challenge. Subjects who met the criteria for standard exclusion from the metacholine challenge were patients with ischemic heart disease and patients who were currently using medications influencing the outcome of bronchial challenge (ie, oral steroids, anticholinergic drugs, and oral or topical [Beta]-antagonists).

Suitable subjects were invited to attend, and they were requested to refrain from drinking beverages containing caffeine for 12 h before attendance. Those taking bronchodilators were requested to refrain from taking them for 12 h (inhaled preparations), 24 h (oral medications), or 48 h (sustained release preparations) before attendance. Attendance was delayed for 6 weeks after any episode of respiratory tract infection or exacerbation of wheezing.

Nonresponders were sent a reminder letter and a second copy of the questionnaire 4 to 6 weeks after receiving the first copy of the questionnaire. A second reminder was sent 1 month later, with an abbreviated questionnaire omitting questions regarding respiratory symptoms. A random sample of persistent nonresponders who were thought to still be living locally was contacted by telephone or home visit and was asked to complete the abbreviated questionnaire.

All participants gave informed signed consent. A 12-lead ECG was performed, and those with evidence of ischemia were excluded from the methacholine challenge. A venous blood sample was taken in order to measure the differential WBC count and the total IgE level. Baseline spirometry was measured by a portable spirometer (Compact; Vitalograph; Buckingham, UK) to obtain a mean of six recordings, which were reproducible within 10%. Subjects with a baseline [FEV.sub.1] of [is less than] 60% predicted[11] were excluded from the bronchial challenge for safety reasons,[12] as were those whose spirometry was not reproducible.

Methacholine challenge was performed by the Newcastle dosimeter method.[12] Doubling doses of nebulized methacholine were inhaled from a mouthpiece at 5-min intervals by the subject, who was seated and wore a nose clip. [FEV.sub.1] was then measured before each subsequent dose in order to obtain a mean of three recordings, which were reproducible to within 10%. End points for the challenge were a 20% decrease in [FEV.sub.1] or an administration of a maximum cumulative dose of 6.4 mg methacholine. Subjects who had a 20% fall in [FEV.sub.1] were given 1 mg inhaled terbutaline (Bricanyl; Astra Pharmaceuticals; Hertfordshire, UK) via a metered-dose inhaler with a plastic spacer device (Nebuhaler; Astra Pharmaceuticals) and remained within the hospital department until the [FEV.sub.1] level had returned to within 90% of the prechallenge level. The repeatability of the methacholine challenge was assessed in 21 subjects who agreed to attend a second challenge 3 to 10 days after the initial challenge.

Data Analysis

Chronic airflow obstruction was defined as an [FEV.sub.1]/FVC ratio of [is less thanor equal to] 65% for subjects aged [is less than] 65 years old; for those aged [is greater than or equal to] 65 years old, a predicted [FEV.sub.1]/FVC ratio was calculated, as described by Enright et al.[13] The result of the methacholine challenge was expressed as the provocative dose of the substance causing a 20% fall in (baseline) [FEV.sub.1] ([PD.sub.20]) and as the slope of the dose-response curve (DRS), a continuous measure of bronchial responsiveness suitable for use in epidemiological surveys.[14] Increased nonspecific bronchial responsiveness was defined as a [PD.sub.20] of [[is less than or equal to]] 200 [micro]g methacholine.[2,15] Because a small number of subjects had an increase in [FEV.sub.1] during the bronchial challenge, a constant of 0.43 was added to all calculated DRS measurements to eliminate negative slopes prior to logarithmic transformation.[5] Values of [PD.sub.20], DRS, serum IgE, and eosinophil count were log transformed to achieve normal distribution.

Because eosinophil counts and serum IgE levels are dependent on age and gender, further analysis was performed using age and gender standardized Z-scores.[16] The Z-score indicates the number of standard deviations by which each serum IgE or eosinophil count differs from the mean value of the appropriate gender and age group (ages 45 to 54 years, 55 to 64 years, 65 to 74 years, and [is greater than] 75 years).

In order to avoid the age and height bias associated with the expression of [FEV.sub.1] as the percent of predicted values in multiple regression calculations, the baseline [FEV.sub.1] was expressed as standardized residuals (SR).[17] These were calculated using the following equation: SR = (recorded value -- predicted value)/ residual standard deviation, where the residual SD is taken from the regression equation used to calculate the predicted values.[18] The prediction equations used for the calculation of SR were derived from urban, white UK adults with a wide age range comparable to that of the current study.[19]

The repeatability of the methacholine challenge was assessed by calculating the coefficient of repeatability, which allows a calculation of 95% units of agreement, between which further repeated measurements would be expected to lie.[20]

The smoking habit of the subjects was quantified as the number of pack-years smoked, where 1 pack-year = 20 cigarettes daily for 1 year.

Subgroups were compared by grouped t test and [chi square] tables. Multiple regression analysis was used to investigate relationships between measures of atopy and pulmonary function. After statistical analysis was performed (Ecstatic; Someware in Vermont; Montpelier, VT), it was found that in all cases, significance was defined at the 5% level.

RESULTS

Of the 783 eligible subjects contacted by mail, 723 subjects returned a questionnaire (response rate, 92.3%). The mean age of those who responded (66.7 years old) was similar to that of the 783 subjects contacted (66.1 years old). There was no significant difference between responders and nonresponders in terms of age and gender distribution (Table 1). Sufficient information for determining eligibility for the methacholine challenge (ie, the full questionnaire) was returned by 508 subjects (64.9% of the eligible population). Of the 508 subjects who responded, 113 subjects were excluded because of ischemic heart disease or medications. The remaining 395 subjects were invited to participate, and 247 of those subjects participated (62.5% of those invited; 31.5% of the total study population). Participants were slightly younger than nonparticipants in the study population (Table 2).

Table 1--Comparison of Questionnaire Responders and Nonresponders

Table 2--Bronchial Challenge: Comparison of Participants and Nonparticipants

(*) Participants vs nonparticipants or study population.

([dagger]) Responders to questionnaire (n = 723).

Of the 247 participants, 217 participants attempted the methacholine challenge. Of these 217 participants, 1 participant did not have reproducible spirometry, 1 participant declined the bronchial challenge, 2 participants had ECG abnormalities, and 26 participants had a predicted baseline [FEV.sub.1] of [is less than] 60%. Nine participants failed to complete the challenge because of fatigue, cough, or spirometry that was not reproducible. Satisfactory results were thus available for 208 participants. Serum IgE measurements were available from 235 participants, and eosinophil counts were available from 231 participants. Missing data represent participants declining blood tests and problems with the sample transport or analysis.

The mean age of those completing the bronchial challenge was 63.7 years old (age range, 45 to 86 years). Of those completing the bronchial challenge, 103 subjects (49.8%) were aged [is greater than] 65 years old, 118 subjects (56.7%) were women, 61 subjects (28.8%) were current smokers, 84 subjects (40.4%) were ex-smokers, 18 subjects (8.7%) reported having asthma, 28 subjects (13.5%) reported having bronchitis, 9 subjects (4.3%) reported having both asthma and bronchitis, and 39 subjects (18.8%) had chronic airflow obstruction. There was no significant difference in smoking habits, prevalence of airflow obstruction, or serum IgE levels between older and younger subjects completing the bronchial challenge.

Twenty-one subjects performed the methacholine challenge on two separate occasions (10 women; mean age, 68.3 years; age range, 54 to 84 years). The repeatability of the challenge results was within [+ or -] 2 doubling doses of methacholine (coefficient of repeatability, 0.21).

Of the 208 subjects who completed the methacholine challenge, 148 subjects (71.1%) achieved a [PD.sub.20], and bronchial responsiveness was increased in 71 subjects (34.1%). Unadjusted data showed no relationship between bronchial responsiveness and age, with no significant linear correlation between either [PD.sub.20] and age (r = -0.04; p = 0.29) or DRS and age (r = 0.08; p = 0.12). Increased bronchial responsiveness was equally common in subjects aged [is less than] 65 years old and [is greater than] 65 years old (Fig 1).

[Figure 1 ILLUSTRATION OMITTED]

Stepwise multiple regression analysis was performed with bronchial responsiveness (expressed as a log dose-response slope) as the dependent variable, and age, gender, pack-years smoked, the airways caliber (expressed as [FEV.sub.1] SR), IgE (expressed as log Z-score), and eosinophils (log Z-score) as independent variables (Table 3). Bronchial responsiveness was positively associated with IgE and with age. Age accounted for 3% of the variability in bronchial responsiveness. There was a strong negative relationship between bronchial responsiveness and the airways caliber. Smoking (number of pack-years smoked) showed a trend toward a positive association with bronchial responsiveness. Gender and eosinophils were not independently associated with bronchial responsiveness. The inclusion of interaction factors for the relationship between the airways caliber and pack-years smoked, and between gender and pack-years smoked, did not affect the results ([R.sup.2] = 0.29).

Table 3--Multiple Regression: Factors Associated With Bronchial Responsiveness (Methacholine [PD.sub.20])(*)

(*) [R.sup.2] = 0.29.

([dagger]) % Var = percentage of variation in the dependent variable attributable to the independent variable.

([double dagger]) Baseline [FEV.sub.1] expressed as SR.

([sections]) Log Z-score.

The relationship between bronchial responsiveness and age was dependent on the method used to adjust the equation to include the baseline airway caliber in the multiple regression analysis. Inclusion of the unadjusted [FEV.sub.1] in the regression equation instead of SR produced a significant negative association between bronchial responsiveness and age (b = -0.02; p = 0.01), whereas when the [FEV.sub.1]/ FVC ratio or the [FEV.sub.1] % predicted was used, the relationship ceased to reach significance ([FEV.sub.1]/ FVC: b = 0.005, p = 0.4; [FEV.sub.1] percent predicted: b = 0.003, p = 0.6).

DISCUSSION

Over one third of the adults in this population had increased bronchial responsiveness (a [PD.sub.20] of [is less than] 200 [micro]g methacholine). This level of bronchial responsiveness has been reported to have a positive predictive value for asthma, approaching 100%.[21] Comparisons with other epidemiological surveys suggest that there is a higher prevalence of bronchial hyperresponsiveness in Manchester than elsewhere: a [PD.sub.20] of [is less than or equal to] 200 [micro]g methacholine was found in 12% of adults aged [is greater than or equal to] 65 years old in New Forest, UK[22] and in 23% of adults in Surrey, UK,[15] compared with 34.6% of adults in Manchester.

The reason for this high prevalence of bronchial hyper-responsiveness in central Manchester is not clear. One reason may be that smoking is very common in this population. Also involved may be "inner-city factors" such as relative poverty in childhood, which leads to poor diet, overcrowding, an increased risk of viral respiratory tract infection, and exposure to high levels of ambient air pollution. Alternatively, methodological differences between studies may be responsible for these results. However, the latter seems unlikely to be the full explanation. A cross-sectional survey using methods almost identical to the current study found a much lower prevalence of measurable bronchial responsiveness in randomly identified men aged 20 to 44 years old.[23]

It is possible that the low attendance rate for the bronchial challenge has resulted in selection bias. Similarly, poor participation rates have been reported for several other population surveys of bronchial responsiveness,[15,24] probably reflecting the reluctance of subjects to undergo the methacholine challenge. However, the high questionnaire response rate suggests that our sample was representative of the selected population. The gender distribution and smoking habits of responders were similar to official estimates for this region.[25,26] Attenders of the bronchial challenge were representative of questionnaire responders except for a small age difference (attenders were younger than nonattenders). Nonetheless, we cannot entirely discount the possibility of selection bias affecting our results.

The association between age and bronchial responsiveness was small, accounting for only 3% of the population variation in bronchial responsiveness. Other published population surveys have reported both decreasing[2,3] and increasing[4-7] bronchial responsiveness with age. The small proportion of older adults included in most other study populations may have obscured a significant relationship. Failure to include the baseline airways caliber in the analysis, or the use of parameters retaining age and gender bias (eg, [FEV.sub.1], percent predicted [FEV.sub.1], and [FEV.sub.1]/FVC ratio) may further account for some of this disagreement. Indeed, the relationship between age and bronchial responsiveness in the current study varied depending on the parameter used to express the airways caliber in the regression analysis. Raw measurements of the airways caliber such as [FEV.sub.1] and [FEV.sub.1]/FVC are strongly related to age and gender, and thus are not suitable as independent variables for the regression analysis. The expression of [FEV.sub.1] as the percent predicted value has been proposed to remove the age and gender bias, but it does so incompletely; because [FEV.sub.1] increases as height increases, and decreases as age increases, the use of percent predicted of [FEV.sub.1] will increase the number of elderly and short individuals appearing to have abnormal results.[17] Because the current study included a large proportion of elderly subjects, the expression of [FEV.sub.1] as SR was chosen as the parameter of the airways caliber least likely to be affected by age bias.

Few longitudinal studies of bronchial responsiveness have been performed. Sparrow et al[5] reported the results of longitudinal change in bronchial responsiveness over a period of 3 years as part of the Normative Aging Study. During that period, there was considerable intrasubject variability in bronchial challenge results, with no evidence of a trend toward increasing bronchial responsiveness. However, 60% of the eligible population refused to participate or were excluded from the methacholine challenge in this study, and the follow-up period was short. In addition, increased bronchial responsiveness at the baseline predicted a new onset of wheeze during the next 3 years.[27] A relationship between increased bronchial responsiveness and age was found only in former smokers, but not in current smokers or in subjects who had never smoked.[28] In the current study, smoking habits (expressed as pack-years) were included in the multiple regression equation to take into account the effect of smoking on bronchial responsiveness. An independent relationship between pack-years smoked and bronchial responsiveness was not detected.

It has been suggested that changes in bronchial responsiveness with age may be the result of alterations in the associations between bronchial responsiveness, atopy, and smoking.[6] In the current study, the interaction between age and smoking habit was not significantly associated with bronchial responsiveness. Furthermore, we found no evidence of a decrease in the strength of the association between atopy and bronchial responsiveness with increasing age.[29]

An increase in the prevalence of bronchial hyperresponsiveness with increasing age is biologically plausible. Although the pathogenesis of increased bronchial responsiveness in asthma is not clear, several mechanisms have been proposed. These include inflammation of the bronchial wall[30] and altered autonomic control of the airways with impaired [Beta]-adrenoceptor activity.[31-33] A reduction in [Beta]-adrenoceptor affinity has also been identified as part of the normal aging process,[34-36] raising the possibility that an increase in bronchial responsiveness is an inevitable part of the aging process.[37] However, longitudinal studies of bronchial responsiveness and [Beta]-adrenoceptor function would be necessary to confirm this hypothesis.

In summary, we have found a high prevalence of increased bronchial responsiveness to methacholine in a random sample of white adults aged 45 to 86 years old living in an urban environment. Bronchial responsiveness in this population shows a weak independent association with age.

ACKNOWLEDGMENTS: The authors thank the British Geriatrics Society and Central Manchester Healthcare Trust for funding this project, the Institute of Clinical Physiology at Manchester Royal Infirmary for the loan of equipment, and Acorn Nebulisers Ltd for supplying nebulizers. We are also indebted to the following general practitioners for allowing us to study their, patients: Dr. P. Beresford, Dr. S. Elliot, Dr. P. Harris, Dr. S. Hilton, Dr. A. Hutton, Dr. H. MacDonald, Dr. L. Reynolds, and Dr. I. Sethi.

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(*) From the University Department of Medicine for the Elderly Barnes Hospital, Manchester, UK.

Supported by the Central Manchester Healthcare Trust (funding), British Geriatrics Society (funding), and Acorn Nebulisers Ltd (equipment).

Manuscript received February 25, 1998; revision accepted September 10, 1998.

Correspondence to: DS Renwick, MD, Department of Medicine for the Elderly, Camborne/Redruth Community Hospital, Barncoose Terrace, Redruth, Cornwall TR15 3ER, UK

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